Fragile X Syndrome

Author: Dr Shubha R. Phadke

Creation date: February 2005

Scientific editor: Prof Koenraad Devriendt

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,
India. Email: shubha@sgpgi.ac.in

Abstract
Key words
History
Etiology
Prevalence of fragile X syndrome
Clinical features
Diagnosis
Management
Genetics of Fragile X syndrome:
Genetic Counseling
Prenatal diagnosis
Reference

Abstract
Fragile X syndrome is the most frequent cause of inherited mental retardation. It is caused by a dynamic
mutation i.e. the progressive expansion of polymeric (CGG)n trinucleotide repeats located in the non
coding region at the 5 end of the FMR1 gene at Xq 27.3. It is an X linked disorder; the manifestations are
seen in all of carrier males and in 35% of carrier females. This type of mode of inheritance is described as
X linked semidominant or X linked dominant with decreased penetrance. The clinical features other than
mental retardation include subtle dysmorphism, behavioral abnormalities and macroorchidism in
postpubertal males. The phenotype being subtle, clinical diagnosis may be difficult especially in young
children. Hence, all cases of mental retardation without obvious cause should be tested for fragile X
syndrome, it is often the only way to identify fragile X syndrome cases. The parents and relatives of such
a case need to be offered genetic counseling to prevent the recurrence of fragile X syndrome in the
family. The cytogenetic and molecular diagnostic tests are available; the latter replacing the formers over
the years. Polymerase chain reaction based tests are used for screening and Southern blot hybridization
is the diagnostic test for detections of mutation and premutation. Prenatal diagnosis is possible by
carrying out Southern blot hybridization on samples of chorionic villi or amniotic fluid. The complexities
due to premutation and variable severity of manifestations in carrier females need to be understood while
counseling families with fragile X syndrome.

Key words
Fragile X syndrome, mutations, premutations, X linked semidominant, mental retardation, trinucleotide
repeat disorder, dynamic mutation, genetic counseling.

males. They and their mother expressed a

History constriction at the end of the long arm of the X
The increased incidence of males in mentally chromosome. This fragile site on X
retarded populations as compared to the chromosome gave the name fragile X syndrome
females was noted for a long time (1). In 1943, to the disorder. The causative gene for fragile X
Martin and Bell(2) described a family of sex linked syndrome is FMR-1 (for Fragile site Mental
mental retardation without dysmorphic features. Retardation-1).and was identified in 1991, by Fu
(3)
In 1969, Lubs observed a marker X et al (4).
chromosome in a family with mentally retarded

Phadke SR. Fragile X Syndrome. Orphanet encyclopedia, February 2005.

http://www.orpha.net/data/patho/GB/uk-Fragile-X.pdf 1
Etiology
The chromosomal abnormality; namely Fragile
site on Xq27.3 is used as a diagnostic marker for
fragile X syndrome. But the disorder is not a
chromosomal disorder. It is caused by mutation
in FMR-1 gene on X chromosome at Xq27.3.
Fragile X syndrome belongs to a group of
disorders caused by expansion of triplet repeats.
Expansion of trinucleotide repeats has been
identified as a common mechanism of hereditary
neurodegenerative diseases including spinal and
bulbar muscular atrophy (Kennedy disease),
Huntington's disease, dentatorubral-
pallidoluysian atrophy (DRPLA), Machado-
Joseph disease (MJD), fragile X syndrome,
myotonic dystrophy and Friedreich's ataxia.
Almost all cases of fragile X syndrome are
caused by expansion of CGG repeats in the 5
untranslated region of the FMR-1 gene (1).
Normal individuals have 6 to 50 CGG repeats at
this site. These repeat are stably transmitted
from generation to generation. In individuals with
fragile X syndrome the number of repeats is
increased to more than 200. When the number is
more than 200, the FMR-1 gene gets methylated
and becomes nonfunctional. The individuals with
CGG repeat number between 50 and 200 are
known as premutation carriers. Carriers of
premutation do not have mental retardation and
male premutation carriers are known as Normal
Transmitting Males (NTM).
The allele with CGG repeat number of more than
200 is known as a full mutation. All males with
full mutation are mentally retarded. About half of
females with full mutation have mental
subnormality or some mild phenotypic features
of fragile X syndrome.
A small group of cases of fragile X syndrome are
reported due to intragenic deletion or point
mutation in the FMR-1 gene (5, 6).
Prevalence of fragile X syndrome
Fragile X mental retardation has been detected
in all populations and ethnic groups. Most of the
studies give prevalence of Fragile X syndrome
as 0.5 to 3% of mentally retarded males of
unknown etiology (7). The higher prevalence up to
11% have also been reported; possibly due to
strict selection criteria. In general population, the
prevalence of fragile X syndrome is found to be
around in 1 in 4000 males (8) For females, recent
large studies have established prevalence of
premutation carriers as 1/260 in general
population(9).
Clinical features
Phenotype in males
The most prominent feature and significant
problem of fragile X syndrome is mental
retardation. The associated dysmorphic features
are subtle making the clinical diagnosis difficult.
Phadke SR. Fragile X Syndrome. Orphanet encyclopedia, February 2005.
http://www.orpha.net/data/patho/GB/uk-Fragile-X.pdf
The face is long with prominent mandible and
large ears. The phenotype is subtle in young
(10)
children and evolves with age.
Macroorchidism (testicular size more than 30 ml)
is an important feature in postpubertal males.
However, it is not present in all fragile X
syndrome males nor it is specific for fragile X
syndrome. Hyperextensibility of finger joints,
pectus excavatum, mitral valve prolapse,
strabismus and epilepsy are other possibly seen
(19)
features
Behavioral Phenotype
Mental retardation in fragile X syndrome males
varies from mild to profound with most affected
males being moderate to severely retarded (11) . A
number of behavioral characteristics associated
with fragile X syndrome have been described.
They include hyperactivity, short attention span,
stereotypic behavior (hand flapping, hand
rubbing, preservative speech, echolalia), poor
eye contact, tactile defensiveness and anxiety
related to social contact. Many of these features
suggest the possibility of autism.
Manifestations in females
About half of the females with full mutation show
some manifestation of fragile X syndrome (12). But
females are usually less severely affected than
males.
Manifestation in Premutation carriers
Premutation carriers were supposed to be
asymptomatic carriers and always clinically
normal. Recently a syndrome of tremor, ataxia
and cognitive decline is reported in premutation
carriers. The penetrance of this syndrome
increases with age and 75% of premutation
carrier beyond 80 years have intentional tremors
and gait ataxia (13,14). Twenty eight percent of
females with premutation experience premature
ovarian failure(15).
Diagnosis
Due to lack of clinical diagnostic criteria, simple
scoring systems have been developed to select
individuals for fragile X syndrome testing (16). But
these scoring systems are mostly useful for
population based studies. As the diagnosis of
each case is very important for the family, every
child with unexplained mental retardation should
be tested for fragile X syndrome.
There are two methods for diagnosis. One is
based on chromosomal study to demonstrate
fragile X chromosome under special folic acid
deficient culture conditions. The cytogenetic
tests (based on demonstration of fragile X
chromosome) can be false negative (due to
inappropriate culture condition) or false positive
(due to fragile X E site near the fragile X A site of
fragile X syndrome). The molecular (DNA) tests
are of two types. The screening tests are
2
polymerase chain reaction (PCR) based and
easy. The cases selected by PCR based test
need to be confirmed by Southern blot
hybridization. Southern blot hybridization detects
mutation as well as pre mutation in males and
females.
Some fragile X syndrome males have full
mutation in some cells of the body and
premutation in some cells of the body. Such
male are known as mosaics and may have less
(9-18)
severe intellectual handicap . Mosaics for
(18)
methylation are also known
A diagnostic test based on use of antibody to
FMR protein (product of FMR-1 gene) to detect
presence or absence of FMR protein in
lymphocytes or hair root cells is also possible (17).
This test can be used to diagnose affected
males; but is not useful to detect premutation
carrier and female carrier of full mutation.
Management
At present there is no cure for fragile X
syndrome. A wide variety of measures are used
to take care of their special educational needs
and to make the affected individuals
independent and integrate in the society as
much as possible. Pharmacological agents like
antidepressants, anticonvulsants are used
whenever indicated. The families should be
cautioned regarding claims of utility of
megavitamins or alternate forms of therapy for
cure of mental retardation.
Genetics of Fragile X syndrome
Presence of premutation and variable
expression in female carrier make genetic
counseling for fragile X syndrome difficult. It is
essential to understand the complexities of
genetic aspects of fragile X syndrome before
counseling a family and a carrier of fragile X
syndrome. The premutation carriers have CGG
repeats varying from 50 to 200 in number. The
premutation alleles with such intermediate
number of repeats are unstable. When
transmitted from one generation to the next
generation through a female, the number of
repeats increases. If the number of repeats
becomes more than 200, the premutation is said
to have got converted to full mutation. The
chance that a premutation will get converted to
full mutation increases as the number of repeats
(19)
in the premutation allele increases . The
increase in the size of repeats occurs only when
the premutation is transmitted by a female.
When the male transmits the premutation to the
next generation, the number of repeats does not
increase and thus, there is no risk of fragile X
syndrome in the offsprings of a premutation
carrier male (also known as normal transmitting
male - NTM). Thus, NTM is more likely to have
affected grandsons than affected brother. This
fact was observed long before the mutation and
Phadke SR. Fragile X Syndrome. Orphanet encyclopedia, February 2005.
http://www.orpha.net/data/patho/GB/uk-Fragile-X.pdf
premutation were identified and was known as
Sherman Paradox.
Genetic Counseling
Associated mental retardation and high risk of
recurrence makes genetic counseling essential
for the families with fragile X syndrome. With the
availability of molecular tests, carrier detection
and prenatal diagnosis is possible. The most
important step is the diagnosis of the affected
case. All mentally retarded children need to be
investigated for fragile X syndrome. The mother
of an individual with fragile X syndrome is an
obligate carrier. She may have full mutation or
premutation. The chance that she will pass on
the X chromosome with mutation (or premutation
as the case may be) to her sons or daughters is
50%. So the chance that her offsprings will not
inherit the X chromosome with mutation (and will
not be affected) is 50%. If the mother is a carrier
of full mutations, she will transmit it to 50% of her
sons who will be affected. She will also transmit
the mutation to 50% of her daughters, but there
is no way to predict whether the daughter with
full mutation will have clinical manifestation and
if yes, what will be the severity of mental
handicap. This is because the severity of the
manifestations varies greatly in the females with
full mutation; possibly depending on the X
inactivation pattern.
If the mother is a carrier of premutation, the
chance that her offsprings will inherit the normal
X chromosome is 50%. The rest 50% will inherit
the other chromosome. But whether the
premutation will get changed to full mutation will
depend on the number of repeats in the
premutation allele of the mother. If the number of
repeats in the mother is between 55 and 59, the
risk of premutation getting converted to full
mutation is 5.4%. The risk increases with
increasing number of repeats and becomes
almost 100% when the number of repeats in the
(18)
premuation allele is more than 100 . If the
number of repeats in the mother is between 60
and 80; the risk of the premutation getting
converted to the full mutation varies from 19% to
50%. For the repeat numbers between 80 and
100; the risk varies from 73 to 87%.
The daughters of a carrier woman and female
relatives on the maternal side (sisters, sisters
daughters) need to be tested for carrier
detection. An attempt should be made to
educate the family to discuss issue with their
relatives about the necessity of carrier detection
and genetic counseling to prevent recurrence of
mentally handicapped children in the family(19).
Prenatal diagnosis
Carrier females need to be provided genetic
counseling and offered prenatal diagnosis. The
reliable prenatal diagnosis is done by Southern
blot analysis in the DNA sample obtained from
3
chorionic villi or amniotic fluid. Birth of an
affected child can be avoided by terminating
pregnancy if the fetus is found to carry a full
mutation.
It should be clear to the family and the counselor
that the phenotype and intelligence of a female
fetus with full mutation can not be predicted by
any prenatal tests and about 50% female carrier
of full mutation are phenotypically normal.
Fragile X mental retardation being one of the
leading causes of mental retardation, screening
of general population for identification of carrier
females and offering them prenatal diagnosis for
prevention of birth of mentally handicapped child
has also been tried and found feasible (20).
Fragile X-associated tremor/ataxia syndrome
(FXTAS), a neurodegenerative disorder, was
described recently among male carriers of
expanded alleles (55-200 CGG repeats;
premutation range) of the fragile X mental
retardation 1 (FMR1) gene. Major features of the
syndrome include intention tremor, gait ataxia,
and parkinsonism in men over 50 years of age.
This disorder is believed to be relatively
common, possibly affecting 1 in 3,000 men over
the age of 50 years in the general population.
This raises the possibility that some patients
presenting with essential tremor (ET) may harbor
expanded FMR1 alleles. Nowadays, with the
finding that carrier males are at risk for fragile-X-
associated tremor/ataxia syndrome (FXTAS),
screening has become less evident, since it may
lead to unwanted presymptomatic diagnosis for
this disorder(21).
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